CN114957110A - 一种抗病毒化合物及其制备方法和应用 - Google Patents
一种抗病毒化合物及其制备方法和应用 Download PDFInfo
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- CN114957110A CN114957110A CN202210167461.2A CN202210167461A CN114957110A CN 114957110 A CN114957110 A CN 114957110A CN 202210167461 A CN202210167461 A CN 202210167461A CN 114957110 A CN114957110 A CN 114957110A
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- quinolyl
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 229940037525 nasal preparations Drugs 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960001462 sodium cyclamate Drugs 0.000 description 1
- 229940005573 sodium fumarate Drugs 0.000 description 1
- 235000019294 sodium fumarate Nutrition 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229940013618 stevioside Drugs 0.000 description 1
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 description 1
- 235000019202 steviosides Nutrition 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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Abstract
Description
技术领域
本发明涉及药物化学技术领域,具体涉及一种抗病毒化合物及其制备方法和应用,特别是一种可作为 PLPro抑制剂的抗冠状病毒化合物及其制备方法和应用。
背景技术
人类患有的许多重要传染病都是由病毒造成的。这些疾病包括狂犬病、天花、脊髓灰质炎、肝炎、肺炎、黄热病、免疫缺陷和各种脑炎病,它们中的许多是高度传染性的且会产生急性不适,且常常是致命的,其它的例如风疹和巨细胞病毒会造成先天畸形。冠状病毒是一个大型病毒家族,在目前已知的正链RNA病毒中基因组是最大的。根据宿主、血清型基因序列以及结构的不同可将冠状病毒分为四类:α类、β类、γ类和δ类。在这四类中,α类、β类只会感染哺乳动物,γ类和δ类主要感染鸟类;α属冠状病毒包括人冠状病毒(HCoV-229E、HCoV-NL63)、长翼蝠冠状病毒(HKU1、HKU8)、犬冠状病毒(CCoV)和猫冠状病毒(FCoV)等;β属冠状病毒包括人冠状病毒(HCoV-OC43、HCoV-HKU1)、新型冠状病毒(SARS-CoV-2)、SARS冠状病毒(SARS-CoV)、中东呼吸综合征冠状病毒(MERS-CoV)、鼠冠状病毒、果蝠冠状病毒HKU9等;γ类冠状病毒主要包括禽冠状病毒如鸡传染性支气管炎病毒(IBV);δ属冠状病毒包括夜莺冠状病毒(BuCoV HKU11)、绣眼鸟冠状病毒(WECoV)、野鸭冠状病毒(WiCoV)、黑水鸡冠状病毒(CMCoV)等。
木瓜样蛋白酶(papain-like protease,PLPro)是表达在冠状病毒5’末端基因组nsp3上的水解酶,主要功能为酶切多聚蛋白pp1a上nsp1-2,nsp2-3,nsp3-4之间特异性四肽结构LXGG,该多聚蛋白需要被水解后成为成熟的功能蛋白,因此是冠状病毒增殖的关键蛋白,同样重要的是,PLpro可以切割宿主细胞关键免疫蛋白的泛素单元,从而保护冠状病毒规避宿主细胞的免疫攻击。因此,抑制冠状病毒的PLPro蛋白不但能够抑制冠状病毒的增殖,也能增强宿主细胞免疫系统对于冠状病毒的监控,从而减少细胞因子风暴。PLPro对于病毒的生命周期至关重要,可以作为抗冠状病毒药物设计筛选的潜在靶点。已经开发了不同化学结构的PLpro抑制剂,但抑制活性仍有待进一步提高。
发明内容
本发明提供一种化合物,其具有以下结构:
其中,
Ar选自:萘基、喹啉基、异喹啉基或喹唑啉基,其中萘基、喹啉基、异喹啉基或喹唑啉基中的氢原子可以任选地被C1-C6烷基、-NH2、-OH、-OC1-C6烷基、-CH2X、-CHX2、-CX3取代;
L1选自:C1-C6亚烷基、-CO-、-SO2-;
A1、A2、A3、A4和A5独立地选自C或N,且当A1、A2、A3、A4或A5为N原子时,与之相连的R1、R2、R3、 R4或R5不存在;
R1、R2、R3、R4和R5独立地选自:H、C1-C6烷基、-L2-NR9R10、-L2-OH、-L2-OC1-C6烷基、-CN、-X、-CH2X、 -CHX2、-CX3;或者,R1、R2、R3、R4和R5中的两者与其连接的原子一起形成杂环基;
L2选自:单键、C1-C6亚烷基、-CO-、-SO2-、-NHCO-、-NH-SO2-;
R9和R10独立地选自:H、C1-C6烷基、-CH2X、-CHX2、-SO2(C1-C6烷基)、-CX3、-L3-NR11R12、含氮杂环基;
R11和R12独立地选自:H、C1-C6烷基、-CH2X、-CHX2、-SO2(C1-C6烷基)、-CX3、-CO(C1-C6烷基);
X选自:F、Cl、Br、I;
R6选自:H、C1-C6烷基;
W1和W2独立地选自:C、N、O;且当W1或W2为O时,相应的R7或R8不存在;
R7和R8独立地选自:H、(=O)、C1-C6烷基、-X、-CH2X、-CHX2、-CX3、羟基、-OC1-C6烷基。
具体地,上述萘基可以为1-萘基或2-萘基。
具体地,上述喹啉基可以为2-喹啉基、3-喹啉基、4-喹啉基、5-喹啉基、6-喹啉基、7-喹啉基或8-喹啉基。
具体地,上述异喹啉基可以为1-异喹啉基、3-异喹啉基、4-异喹啉基、5-异喹啉基、6-异喹啉基、7-异喹啉基或 8-异喹啉基。
具体地,上述喹喔啉基可以为2-喹唑啉基、4-喹唑啉基、5-喹唑啉基、6-喹唑啉基、7-喹唑啉基或8-喹唑啉基。
在本发明的一个实施方式中,上式Ⅰ中,Ar为萘基,例如1-萘基或2-萘基,特别是1-萘基。
具体地,R6选自:H、-CH3、-CH2CH3;在本发明的一个实施例中,R6为H。
具体地,W1为C,W2为C;或,W1为C,W2为N;或,W1为C,W2为O。
具体地,R7和R8独立地选自:H、(=O)、C1-3烷基、-CF3、羟基;在本发明的一个实施例中,R7和R8均为H。
具体地,上述化合物可以具有如下结构:
具体地,上式Ⅰ中,A1、A2、A3、A4和A5中N原子数为0-2(例如0、1、2)个。
在本发明的一个实施方式中,A1、A2、A3、A4和A5均为C。
在本发明另一个实施方式中,A1为N,A2、A3、A4和A5为C。
在本发明另一个实施方式中,A2为N,A1、A3、A4和A5为C。
在本发明另一个实施方式中,A3为N,A1、A2、A4和A5为C。
在本发明另一个实施方式中,A4为N,A1、A2、A3和A5为C。
在本发明另一个实施方式中,A5为N,A1、A2、A3和A4为C。
在本发明另一个实施方式中,A1和A2为N,A3、A4和A5为C。
在本发明另一个实施方式中,A1和A3为N,A2、A4和A5为C。
在本发明另一个实施方式中,A1和A4为N,A2、A3和A5为C。
在本发明另一个实施方式中,A1和A5为N,A2、A3和A4为C。
在本发明另一个实施方式中,A2和A3为N,A1、A4和A5为C。
在本发明另一个实施方式中,A2和A4为N,A1、A3和A5为C。
在本发明另一个实施方式中,A2和A5为N,A1、A3和A4为C。
在本发明另一个实施方式中,A3和A4为N,A1、A2和A5为C。
在本发明另一个实施方式中,A3和A5为N,A1、A2和A4为C。
在本发明另一个实施方式中,A4和A5为N,A1、A2和A3为C。
具体地,上述化合物可以具有如下结构:
在本发明的一个实施例中,L1为-CO-或-SO2-。
具体地,L2选自:单键、-CH2-、-SO2-、-NHCO-、-NH-SO2-。
具体地,R11和R12独立地选自:H、-CH3、-CH2CH3、-COCH3、-COCH2CH3。
具体地,R1、R2、R3、R4和R5中的至少一个为-L2-NR7R8。
在本发明另一个实施方式中,R1、R2、R3、R4和R5中相邻的两者与其中间连接的原子一起形成杂环基,例如五至七元杂芳基(例如五元或六元含氮杂芳基),其与环形成稠合环。在本发明的一个实施例中,该杂芳基为部分可以为例如其中R1、R2和R5具有本发明上述相应定义。
具体地,式Ⅴ中,R5选自:H、C1-C6烷基、-CF3,R2为-L2-NR7R8;更具体地,式Ⅴ中,R5选自:H、-CH3、 -CF3,R2选自: 特别是在本发明的一些实施例中,上述化合物具有如下结构:
特别是
本发明还提供上述化合物的药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物。
本发明还提供一种上述化合物的方法,其可以包括如下工艺路线:
具体地,上述步骤(1)中乙基格氏试剂可以为乙基溴化镁。
具体地,上述步骤(1)反应在有机溶剂(如四氢呋喃)中进行。
具体地,上述步骤(1)反应温度为室温。
本发明还提供一种药物组合物,其包含本发明上述化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物,以及一种或多种药学上可接受的辅料。
具体地,上述药物组合物中,本发明上述化合物可以作为唯一的活性成分,也可与一种或多种其它用于相同适应症或不同适应症的活性成分联用,其中,本发明上述化合物与该其他活性成分可配制用于同时、单独或顺序给药(simultaneous,separate orsequential administration)。
具体地,上述药学上可接受的辅料可以包括甜味剂(具体如,蔗糖、木糖醇、低聚果糖、甜蜜素、甜菊糖、阿斯巴甜等)、芳香剂(如香料、香精等)、胶浆剂(具体如,海藻酸钠、阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素钠等)、澄清剂(具体如,壳聚糖、明胶等)、防腐剂(具体如,苯甲酸及其盐、山梨酸及其盐、尼泊金类系列等)、崩解剂(具体如,低取代羟丙基纤维素、交聚维酮、羧基乙酸淀粉钠、交联羧甲基纤维素钠、淀粉等)、粘结剂(具体如,羟丙基纤维素、羟丙甲纤维素、聚维酮、共聚维酮、预胶凝淀粉等)、润滑剂(具体如,硬脂酸、硬脂酸镁、富马酰硬脂酸钠等)、润湿剂(具体如,聚氧乙烯山梨糖醇酐脂肪酸酯、泊洛沙姆、聚氧乙烯蓖麻油衍生物等)、悬浮剂(具体如,羟丙甲纤维素、羟丙基纤维素、聚维酮、共聚维酮、羧甲基纤维素钠、甲基纤维素等)、稳定剂(具体如,柠檬酸、富马酸、琥珀酸等)、填充剂(具体如,淀粉、蔗糖、乳糖、微晶纤维素等)、粘合剂(具体如,纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮等)等中的一种或多种。
具体地,上述药物组合物可以采用任意的剂型或给药形式,本领域技术人员可以根据情况选用,包括,但不限于,片剂(包括糖衣片剂、膜包衣片剂、舌下片剂、口腔崩解片、口腔片剂等等)、丸剂、粉剂、颗粒剂、胶囊剂(包括软胶囊、微胶囊)、锭剂、糖浆剂、溶液剂、乳剂、混悬剂、控制释放制剂(例如,瞬时释放制剂、缓释制剂、缓释微囊)、气雾剂、膜剂(例如,口服崩解膜剂、口腔粘膜-粘附膜剂)、注射剂(例如,皮下注射、静脉注射、肌内注射、腹膜内注射)、静脉滴注剂、透皮吸收制剂、软膏剂、洗剂、粘附制剂、栓剂(例如,直肠栓剂、阴道栓剂)、小药丸、鼻制剂、肺制剂(吸入剂)、眼睛滴剂等等;给药形式例如,口服给药或胃肠外给药(例如,静脉内、肌内、皮下、器官内、鼻内、皮内、滴注、脑内、直肠内等给药形式)。
本发明还提供上述化合物及其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物、上述药物组合物作为PLpro抑制剂的应用,例如作为抗病毒药物的应用。
本发明还提供上述化合物及其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物、上述药物组合物在制备预防和/或治疗由病毒感染引起或病毒感染相关的疾病或病症的药物中的应用。
具体地,上述应用中,化合物、药物组合物具有本发明上述相应定义。
在本发明的一个实施方式中,上述病毒为冠状病毒,例如,HCoV-229E、HCoV-OC43、HCoV-NL63、 HCoV-HKU、SARS-CoV、MERS-CoV、SARS-CoV-2等,特别是SARS-CoV、MERS-CoV、SARS-CoV-2。
具体地,上述疾病或病症为冠状病毒感染引起或冠状病毒感染相关的疾病或病症,例如COVID-19、SARS、 MERS等。
本发明还提供一种预防和/或治疗由病毒感染引起或病毒感染相关的疾病或病症的方法,其包括对受试者给予有效量的本发明上述化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物,或本发明上述药物组合物的步骤。
具体地,上述方法中,化合物、药物组合物、疾病或病症具有本发明上述相应定义。
特别是,上述疾病或病症为冠状病毒感染引起或冠状病毒感染相关的疾病或病症,例如COVID-19、SARS、 MERS等。
具体地,上述受试者为动物;在本发明的一个实施方式中,上述受试者为哺乳动物,如人类、猴、猫、狗、鼠、蝙蝠等;在本发明的另一个实施方式中,上述受试者为鸟类。
本发明提供了一种结构新颖的化合物,其可作为PLPro抑制剂,活性高,可用于广谱抗病毒,特别是冠状病毒(例如SARS-CoV、MERS-CoV、SARS-CoV-2),在药物领域具有非常好的应用前景和价值。
附图说明
图1所示为实施例2制备的化合物的抑制率曲线。
图2所示为实施例35制备的化合物的抑制率曲线。
图3所示为阳性对照化合物GRL0617的抑制率曲线。
具体实施方式
除非另有定义,本发明中所使用的所有科学和技术术语具有与本发明涉及技术领域的技术人员通常理解的相同的含义。
术语“烷基”是指直链或支链的且不含不饱和键的烃链自由基,且该烃链自由基以单键与分子其它部分连接。典型的烷基基团含有1至12(例如1、2、3、4、5、6、7、8、9、10、11、12)个碳原子,如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、正己基、异己基等。如果烷基被环烷基取代,其相应为“环烷基烷基”自由基,如环丙基甲基、环丙基乙基、环丁基甲基、环戊基甲基、环己基甲基等。如果烷基被芳基取代,那么其相应为“芳烷基”自由基,如苄基、二苯甲基或苯乙基。如果烷基被杂环基取代,那么其相应为“杂环基烷基”自由基。“亚烷基”通常是指具有两个自由价键的烷二基,典型的亚烷基含有1至12(例如1、2、3、4、5、6、7、8、9、10、11、12)个碳原子,如亚甲基、亚乙基、亚丙基、亚丁基等。
术语“烷氧基”是指羟基中的氢被烷基取代后形成的取代基,典型的烷氧基含有1至12(例如1、2、3、4、5、6、7、8、9、10、11、12)个碳原子,如甲氧基、乙氧基、丙氧基、丁氧基等。
术语“环烷基”是指饱和或部分饱和的(特别是饱和的)单环或多环基团,其可以含1至4个单环和/或稠环、含3-18个碳原子,优选3-10(例如3、4、5、6、7、8、9、10)个碳原子,如环丙基、环丁基、环戊基、环己基或金刚烷基等。
术语“芳基”是指单环或多环自由基,包括含单芳基基团和/或稠芳基基团的多环自由基,如包含1-3个单环或稠环及6-18(例如6、8、10、12、14、16、18)个碳环原子,典型的芳基为含有6-12个碳环原子的芳基,如苯基、萘基、联苯基、茚基等。“亚芳基”是指通过移除两个氢原子而衍生自芳族烃的二价基团。
术语“杂环基”包括含1至3个单环和/或稠环及3至约18个环原子的杂芳香族基团和杂脂环基团。优选的杂芳香族基团和杂脂环基团含5至约10个环原子。本发明的化合物中的合适的杂芳基含1、2或3种杂原子,所述杂原子选自N、O或S原子。杂芳基的实例,例如,但不限于,香豆素,包括8-香豆素、喹啉基,包括8-喹啉基、异喹啉基、吡啶基、吡嗪基、吡唑基、嘧啶基、呋喃基、吡咯基、噻吩基、噻唑基、异噻唑基、三唑基、四唑基、异恶唑基、恶唑基、咪唑基、吲哚基、异吲哚基、吲唑基、吲嗪基、酞嗪基、蝶啶基、嘌呤基、恶二唑基、噻二唑基、呋吖基、哒嗪基、三嗪基,噌啉基、苯并咪唑基、苯并呋喃基、苯并呋吖基、苯并噻吩基、苯并噻唑基、苯并恶唑基、喹唑啉基、喹喔啉基、萘啶基和呋喃并吡啶基,等。本发明的化合物中的合适的杂脂环基团含1、2或3种杂原子,所述杂原子选自N、O或S原子。杂脂环基团的实例,例如,但不限于,吡咯烷基、四氢呋喃基、二氢呋喃、四氢噻吩基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、氧硫杂环己烷基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、高哌啶基、氧杂环丙烷基、硫杂环丙烷基、吖庚因基、氧氮杂环庚基基、二吖庚因基、三吖庚因基、1,2,3,6-四氢吡啶基、2-吡咯啉基、3-吡咯啉基,二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己烷基、1,3-二氧戊环基、吡唑啉基、二噻烷基、二硫戊环基、二氢吡喃基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、 3H-吲哚基和喹嗪基,等。
上述基团可以在一个或多个可用的位置被一个或多个合适的基团所取代,所述基团如:OR'、=O、SR'、 SOR'、SO2R'、OSO2R'、OSO3R'、NO2、NHR'、N(R')2、=N-R'、N(R')COR'、N(COR')2、N(R')SO2R'、 N(R')C(=NR')N(R')R'、N3、CN、卤素、COR'、COOR'、OCOR'、OCOOR'、OCONHR'、OCON(R')2、CONHR'、 CON(R')2、CON(R')OR'、CON(R')SO2R'、PO(OR')2、PO(OR')R'、PO(OR')(N(R')R')、C1-C12烷基、C3-C10环烷基、C2-C12烯基、C2-C12炔基、芳基和杂环基,其中每个R'基团各自独立地选自:氢、OH、NO2、NH2、SH、 CN、卤素、COH、CO烷基、COOH、C1-C12烷基、C3-C10环烷基、C2-C12烯基、C2-C12炔基、芳基和杂环基。其中,这些基团本身被取代,取代基可选自前述列表。
“卤素”是指溴、氯、碘或氟。卤代烷基是指烷基上的氢原子被卤素原子(F、Cl、Br、I)取代的基团,如-CH2Rh、-CHRh2、-CRh3,其中,Rh为F、Cl、Br或I;如-CF3。
术语“药学上可接受的盐”是指理论上无毒、刺激性及过敏反应的,并且能够实现或提供药物分子临床上可接受的药代动力学性质、吸收、分布及代谢性质,可达到预期目的的酸性盐或碱性盐。本发明所述的盐包括化合物的酸性基团、碱性基团或两性基团药学上可接受的酸性盐或碱性盐。适宜的盐的列表可参见 S.M.Birge,et al.,J.Pharm.Sci.,66,1-19(1977)。
本发明所述的药学上可接受的盐中包括酸加成盐和碱加成盐。
所述的酸加成盐包括但不限于来自无机酸诸如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸和膦酸的盐,以及来自有机酸如脂肪族单羧酸和二羧酸、苯基取代的链烷酸、羟基链烷酸、链烷二酸、芳香酸和脂肪族和芳香族磺酸的盐。因此,这些盐包括但不限于硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、盐酸盐、氢溴酸盐、碘酸盐、乙酸盐、丙酸盐、辛酸盐、异丁酸盐、乙二酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、苦杏仁酸盐、苯甲酸盐、氯代苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、酞酸盐、苯磺酸盐、甲苯磺酸盐、苯基乙酸盐、柠檬酸盐、乳酸盐、马来酸盐、酒石酸盐和甲磺酸盐,还包含氨基酸的盐如精氨酸盐、葡糖酸盐、半乳糖醛酸盐等。酸加成盐可以通过以常规方式使游离碱形式与足够量的所需酸接触形成盐的方式制备。可通过使盐形式与碱接触重新生成游离碱形式,并且以常规方式分离该游离碱。
本发明所述的碱加成盐是指与金属或者胺形成的盐,诸如碱金属和碱土金属的氢氧化物,或者与有机胺形成。用作阳离子的金属的例子包括但不限于钠、钾、镁、和钙。适当的胺的例子包括但是不限于N,N′-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺(乙烷-1,2-二胺)、N-甲基葡糖胺和普鲁卡因。碱加成盐可通过以常规方式使游离酸形式与足够量的所需碱接触形成盐的方式制备。可通过使盐形式与酸接触重新生成游离酸形式,并且以常规方式分离游离酸。
术语“溶剂化物”应理解为是指本发明的化合物的任意形式,其中所述化合物通过非共价键与另一个分子相连(通常为极性溶剂),特别是包括水化物和醇化物,例如甲醇化物。优选的溶剂化物为水化物。
术语“前体药物”使用其广义含义,并涵盖在体内可转化成本发明化合物的衍生物。前体药物的例子包括但不限于化合物的衍生物和代谢物,包括可生物水解的部分,如可生物水解的酰胺、可生物水解的酯、可生物水解的氨基甲酸酯、可生物水解的碳酸酯、可生物水解的酰脲和可生物水解的磷酸酯类似物。优选地,具有羧基官能团的前体药物为羧酸的低级烷基酯。所述的羧酸酯易由存在于分子中的任何羧酸部分进行酯化得到。前体药物通常可由已知方法来制备,如在Burger“Medicinal Chemistry and Drug Discovery第六版(Donald J.Abraham ed.,2001,Wiley)和“Design and Applications of Prodrugs”(H.Bundgaard ed.,1985,Harwood Academic Publishers)中描述的方法。
本文所涉及的任何化合物均旨在代表这样的特定化合物及其某些变形或某些形式。特别地,在这里所涉及的化合物可能具有不对称中心,并因此存在不同的对映体或非对映体形式。由此,本文涉及的任何给定的化合物代表外消旋物的任意一种、一种或多种对映体形式、一种或多种非对映体形式、及其混合物。同样地,也可能存在双键的立体异构体或几何异构体,由此在一些情况中,分子可能存在为(E)-异构体或(Z)-异构体(反式和顺式异构体)。如果分子包含多个双键,那么每个双键将具有其自身的立体异构现象,其可以与所述分子的其它双键的立体异构现象相同或不同。此外,本文中涉及的化合物可存在阿托异构体。本文涉及的化合物的所有立体异构体,包括对映体、非对映异构体、几何异构体和阿托异构体、及其混合物,都在本发明的范围内。
本文所引用的各种出版物、专利和公开的专利说明书,其公开内容通过引用整体并入本文。
下面将结合本发明实施例,对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1:
THU101:1H NMR(400MHz,Methanol-d4)δ8.65(d,J=8.5Hz,1H),8.00(d,J=6.0Hz,1H),7.91(d,J= 7.0Hz,1H),7.86(d,J=8.2Hz,1H),7.79(d,J=8.3Hz,1H),7.60(t,J=7.7Hz,1H),7.46(dt,J=15.3,7.6Hz, 2H),7.17(d,J=2.8Hz,1H),6.52(dd,J=6.2,2.8Hz,1H),2.92(s,6H),1.51(t,J=3.5Hz,2H),1.33(t,J=3.5 Hz,2H).13C NMR(101MHz,DMSO-d6)δ146.50,138.04,133.97,132.27,131.56,128.95,128.81,128.10,126.15,125.88,125.59,125.51,123.06,113.39,111.21,56.85,55.72,47.13,44.40,43.92,34.64,24.35,18.30,14.51.MS (ESI,m/z):C21H21N3O,[M+H]+332.17.
实施例2:
THU102:1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.68(d,J=8.3Hz,1H),7.93(d,J=8.0Hz,1H),7.83(d,J =7.6Hz,2H),7.52(ddt,J=29.4,15.2,7.4Hz,3H),6.76(d,J=8.1Hz,1H),6.45(dd,J=8.0,2.5Hz,1H),6.29(d,J=2.5 Hz,1H),4.91(s,2H),1.87(s,3H),1.33(d,J=5.4Hz,2H),1.16(d,J=5.3Hz,2H).13C NMR(101MHz,DMSO-d6)δ 170.49,146.47,138.34,138.16,133.91,132.31,131.03,128.92,128.85,128.03,126.19,125.84,125.69,125.49,121.49, 115.00,112.79,34.34,18.37,14.68.MS(ESI,m/z):C21H20N2O,[M+H]+317.16.
实施例3:
THU103:1H NMR(400MHz,Chloroform-d)δ9.00(s,1H),8.61(d,J=8.5Hz,1H),8.31(dd,J=4.6,1.6Hz,1H), 8.01(dd,J=7.1,1.3Hz,1H),7.89(d,J=8.2Hz,1H),7.80(d,J=8.2Hz,1H),7.64(ddd,J=8.4,6.8,1.4Hz,1H),7.50 (dt,J=8.0,6.5Hz,3H),7.22(dd,J=7.8,4.6Hz,1H),2.68(s,3H),1.57(t,J=3.4Hz,2H),1.44–1.39(m,2H).MS(ESI,m/z):C20H18N2O,[M+H]+303.27.
实施例4:
THU104:1H NMR(400MHz,Chloroform-d)δ8.47(d,J=8.3Hz,1H),8.40–8.32(m,2H),7.94(dd,J=7.7,4.4Hz, 2H),7.84(d,J=8.2Hz,1H),7.64–7.45(m,3H),7.29(s,1H),6.99(d,J=4.9Hz,1H),6.75(s,1H),2.16(s,3H),1.60(t, J=3.6Hz,2H),1.45(t,J=3.6Hz,2H).13C NMR(101MHz,Chloroform-d)δ151.82,147.44,129.04,128.69,128.48,126.21,125.50,123.77,120.23,34.93,16.15,14.80,14.71.MS(ESI,m/z):C20H18N2O,[M+H]+303.25.
实施例5:
THU105:1H NMR(400MHz,Chloroform-d)δ8.99(s,1H),8.49–8.38(m,2H),7.96–7.75(m,4H),6.98(s, 1H),2.42(s,3H),1.59(t,J=4.9Hz,2H),1.45(t,J=4.9Hz,2H).13CNMR(101MHz,Chloroform-d)δ158.98, 158.87,154.47,154.37,136.27,129.87,129.44,129.34,129.21,129.06,128.96,128.85,128.73,126.65,126.43, 125.70,125.48,124.01,35.32,15.02,14.93,14.79.MS(ESI,m/z):C19H17N3O,[M+H]+304.34.
实施例6:
THU106:1H NMR(400MHz,Chloroform-d)δ8.85(s,1H),8.62(d,J=8.5Hz,1H),8.05(d,J=5.6Hz,1H),7.97 (d,J=7.0Hz,1H),7.87(d,J=8.2Hz,1H),7.79(d,J=8.2Hz,1H),7.62(dd,J=8.6,6.8Hz,1H),7.48(dt,J=11.7,7.5 Hz,2H),7.36(d,J=2.4Hz,1H),6.51(dd,J=5.8,2.4Hz,1H),1.60(t,J=5.6Hz,2H),1.40(t,J=5.6Hz,2H).13C NMR(101MHz,Chloroform-d)δ153.84,137.16,133.96,132.13,128.78,128.67,128.22,126.18,125.45,125.38,124.53, 111.00,107.99,53.43,34.17,29.33,14.68.MS(ESI,m/z):C19H17N3O,[M+H]+304.21.
实施例7:
THU107:1H NMR(400MHz,Chloroform-d)δ8.49(d,J=8.4Hz,1H),8.45–8.28(m,2H),8.00-7.85(m,2H), 7.83(d,J=8.3Hz,1H),7.65-7.40(m,3H),7.07(d,J=5.1Hz,1H),6.92(s,1H),2.26(d,J=1.9Hz,3H),1.61(t,J=4.5 Hz,2H),1.44(t,J=4.5Hz,2H).MS(ESI,m/z):C20H18N2O,[M+H]+303.25.
实施例8:
THU108:1H NMR(400MHz,Methanol-d4)δ8.67(d,J=8.5Hz,1H),7.90(dd,J=11.4,8.0Hz,2H),7.80(d,J=8.3Hz,1H),7.61(t,J=7.8Hz,1H),7.47(dt,J=15.8,8.0Hz,3H),7.19(d,J=7.4Hz,1H),6.63(d,J=8.3Hz,1H),1.54 (t,J=7.4Hz,2H),1.33(t,J=7.4Hz,2H).13C NMR(101MHz,Methanol-d4)δ166.25,158.73,137.91,136.91,134.12, 132.08,128.36,128.21,127.91,125.74,125.14,124.72,124.28,111.66,110.35,33.83,13.76.MS(ESI,m/z):C19H17N3O, [M+H]+304.39.
实施例9:
THU109:1H NMR(400MHz,Methanol-d4)δ8.62–8.55(m,1H),8.00-7.90(m,2H),7.87–7.79(m,2H),7.58 (ddd,J=8.4,6.8,1.4Hz,1H),7.54–7.47(m,1H),7.47–7.41(m,1H),6.81(d,J=2.8Hz,1H),2.09(s,3H),1.45(t,J= 3.5Hz,2H),1.34–1.28(m,2H).13CNMR(101MHz,Methanol-d4)δ170.50,142.54,141.95,136.53,135.59,134.14, 132.68,132.06,128.40,127.94,125.72,125.16,124.71,124.34,120.35,34.15,19.00,13.53.MS(ESI,m/z):C20H19N3O, [M+H]+318.18.
实施例10:
THU110:1H NMR(400MHz,Methanol-d4)δ8.66(d,J=8.5Hz,1H),7.93–7.83(m,3H),7.77(d,J=8.2Hz,1H), 7.58(t,J=7.7Hz,1H),7.48(t,J=7.5Hz,1H),7.42(t,J=7.7Hz,1H),6.72(d,J=4.2Hz,2H),1.44(t,J=4.4Hz,2H), 1.32–1.26(m,2H).13C NMR(101MHz,Methanol-d4)δ168.08,159.77,147.04,144.46,136.53,134.11,132.10,128.61, 128.39,127.94,125.71,125.12,124.68,124.32,109.64,106.77,34.25,13.66.MS(ESI,m/z):C19H17N3O, [M+H]+304.26.
实施例11:
THU111:1H NMR(400MHz,Methanol-d4)δ8.70(dd,J=8.5,1.2Hz,1H),7.89(ddd,J=16.0,7.7,1.3Hz,2H), 7.79(d,J=8.3Hz,1H),7.60(ddd,J=8.4,6.8,1.4Hz,1H),7.53–7.37(m,2H),7.13–7.02(m,1H),6.99–6.88(m,2H), 6.78(ddd,J=7.9,2.3,1.2Hz,1H),1.49–1.43(m,2H),1.33–1.26(m,2H).13C NMR(101MHz,Methanol-d4)δ170.28, 147.75,136.96,135.62,134.11,132.17,128.64,128.48,128.32,127.76,125.63,125.05,124.64,124.47,117.77,116.04, 113.34,34.22,13.68.MS(ESI,m/z):C20H18N2O,[M+H]+304.17.
实施例12:
THU112:1H NMR(400MHz,Methanol-d4)δ8.68(d,J=8.5Hz,1H),8.02(d,J=4.8Hz,1H),7.90(dd,J= 15.6,7.6Hz,2H),7.80(d,J=8.3Hz,1H),7.59(s,1H),7.47(d,J=19.8Hz,2H),6.83(s,1H),6.74(d,J=5.3Hz, 1H),3.04(s,6H),1.48(s,2H),1.33(s,2H).13C NMR(101MHz,Methanol-d4)δ168.37,159.32,147.29,143.71, 136.58,134.13,132.11,128.64,128.38,127.92,125.65,125.11,124.66,124.34,108.33,104.15,37.06,34.32,13.65. MS(ESI,m/z):C21H21N3O,[M+H]+332.37.
实施例13:
THU113:1H NMR(400MHz,Chloroform-d)δ8.83(s,1H),8.59(d,J=8.5Hz,1H),7.97(d,J=7.1Hz,1H), 7.88(d,J=8.3Hz,1H),7.79(d,J=8.3Hz,1H),7.61(t,J=7.9Hz,1H),7.53–7.42(m,3H),7.37(dd,J=7.2,2.3 Hz,1H),6.56(dd,J=8.4,2.4Hz,1H),3.07(s,6H),1.61(s,2H),1.41(s,2H).13C NMR(101MHz,Chloroform-d) δ165.08,157.54,147.80,138.16,137.37,134.05,132.12,128.96,128.36,128.15,126.03,125.57,125.40,124.20, 109.77,108.85,37.99,34.02,14.59,14.55.MS(ESI,m/z):C21H21N3O,[M+H]+332.31.
实施例14:
THU114:1H NMR(400MHz,Methanol-d4)δ8.60(d,J=8.4Hz,1H),7.92(dd,J=7.8,3.4Hz,2H),7.84(d, J=8.3Hz,1H),7.77(dd,J=8.0,2.0Hz,1H),7.65-7.56(m,2H),7.54-7.44(m,2H),7.32(d,J=8.1Hz,1H),2.10 (s,3H),1.49(t,J=5.8Hz,2H),1.34(t,J=3.6Hz,2H).13C NMR(100MHz,Methanol-d4)δ168.25,141.87, 140.12,134.40,133.27,132.91,132.02,130.37,128.90,127.79,127.72,127.00,126.30,125.96,125.14,124.85,124.50,35.89,20.76,18.80.MS(ESI,m/z):C21H20N2O3S,[M+H]+381.12.
实施例15:
THU115:1H NMR(400MHz,Methanol-d4)δ8.70(d,J=8.5Hz,1H),7.95(d,J=7.1Hz,1H),7.89(d,J= 8.2Hz,1H),7.81(d,J=8.3Hz,1H),7.75(d,J=9.4Hz,2H),7.66-7.55(m,2H),7.43-7.53(m,3H),4.12(s,2H), 1.49(d,J=6.3Hz,2H),1.36(d,J=5.5Hz,2H).13C NMR(100MHz,Methanol-d4)δ169.32,142.50,134.32, 133.94,133.27,132.91,130.29,128.76,128.57,127.79,127.72,127.31,126.30,125.96,125.14,124.85,124.50,46.33,35.96,18.80.MS(ESI,m/z):C21H20N2O,[M+H]+317.16.
实施例16:
THU116:1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.65(d,J=8.2Hz,1H),8.43(s,1H),7.94(d,J=7.9 Hz,1H),7.88-7.75(m,2H),7.63-7.50(m,2H),7.48(d,J=8.0Hz,1H),7.30(d,J=8.2Hz,1H),7.06(s,1H),6.96 (d,J=8.3Hz,1H),5.77(s,2H),1.94(s,3H),1.34(s,2H),1.17(s,2H).13C NMR(100MHz,Methanol-d4)δ 168.61,156.09,137.72,135.48,135.39,134.40,133.27,132.91,130.48,127.79,127.72,126.30,125.96,125.14,124.85,124.50,121.11,117.46,35.89,20.80,18.80.MS(ESI,m/z):C22H21N3O2,[M+H]+360.16.
实施例17:
THU117:1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),8.65(d,J=8.2Hz,1H),7.94(d,J=7.7Hz,1H), 7.84(t,J=7.4Hz,2H),7.63–7.43(m,3H),7.40(dt,J=8.1,2.1Hz,1H),7.25(d,J=8.1Hz,1H),7.14(d,J=2.2 Hz,1H),3.50(d,J=1.7Hz,6H),2.04(d,J=1.7Hz,3H),1.41(d,J=5.6Hz,2H),1.24–1.19(m,2H).13C NMR (101MHz,DMSO-d6)δ168.45,138.98,137.78,137.74,133.95,132.21,131.93,131.80,131.61,129.37,128.98,128.92,128.25,126.20,125.93,125.54,125.43,43.41,34.64,19.00,14.56,14.52.MS(ESI,m/z):C23H24N2O5S2, [M+H]+473.12.
实施例18:
THU118:1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.64(d,J=8.3Hz,1H),8.20(s,1H),7.92(d,J=8.0 Hz,1H),7.83(d,J=7.4Hz,2H),7.51(ddd,J=27.0,15.4,7.1Hz,3H),7.02(t,J=8.9Hz,1H),6.91(d,J=8.3Hz, 1H),6.80(s,1H),1.86(d,J=2.3Hz,3H),1.34(s,2H),1.19–1.13(m,2H).13C NMR(100MHz,DMSO-d6)δ 167.29,138.75,135.89,134.47,133.00,132.69,132.23,129.92,127.69,127.62,126.10,125.79,124.91,124.63,124.31,121.34,117.71,35.89,20.64,18.60.MS(ESI,m/z):C21H21N3O3S,[M+H]+396.13.
实施例19:
THU119:1H NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.63(d,J=8.2Hz,1H),7.95–7.89(m,1H),7.86– 7.78(m,2H),7.59–7.42(m,3H),6.86(t,J=7.7Hz,1H),6.41(d,J=8.0Hz,1H),6.28(d,J=7.4Hz,1H),4.54(s, 2H),1.74(s,3H),1.38–1.32(m,2H).1.17-1.14(m,2H).MS(ESI,m/z):C21H20N2O,[M+H]+317.16.
实施例20:
THU120:1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.63(d,J=8.3Hz,1H),7.92(dd,J=8.0,1.5Hz, 1H),7.85–7.73(m,2H),7.57(ddd,J=8.4,6.7,1.6Hz,1H),7.51(ddd,J=8.0,6.8,1.3Hz,1H),7.44(dd,J=8.2, 7.1Hz,1H),6.85(d,J=8.3Hz,1H),6.80(d,J=2.2Hz,1H),6.63(dd,J=8.3,2.3Hz,1H),5.75(s,2H),1.29(q,J =4.7,4.3Hz,2H),1.13(q,J=4.8Hz,2H).MS(ESI,m/z):C21H17F3N2O,[M+H]+371.13.
实施例21:
THU121:1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.64(d,J=8.2Hz,1H),7.92(dd,J=7.9,1.6Hz, 1H),7.86–7.76(m,2H),7.61–7.40(m,3H),6.79(t,J=7.7Hz,1H),6.57(dd,J=8.0,1.3Hz,1H),6.21(dd,J= 7.5,1.3Hz,1H),4.87(s,2H),1.69(s,3H),1.32(q,J=4.6,4.1Hz,2H),1.14(q,J=4.7Hz,2H).MS(ESI, m/z):C21H20N2O,[M+H]+317.16.
实施例22:
THU122:1H NMR(400MHz,DMSO-d6)δ8.69(d,J=9.1Hz,2H),7.91(d,J=8.1Hz,1H),7.80(d,J=7.6 Hz,2H),7.57(t,J=7.7Hz,1H),7.51(t,J=7.5Hz,1H),7.44(t,J=7.7Hz,1H),6.94–6.85(m,1H),6.26(d,J= 7.4Hz,2H),5.25(s,2H),2.05(s,3H),1.30(d,J=6.0Hz,2H),1.12(s,2H).MS(ESI,m/z):C21H20N2O, [M+H]+317.16.
实施例23:
THU123:1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.62(d,J=8.4Hz,1H),7.93(d,J=8.0Hz,1H),7.81(dd,J =12.6,7.9Hz,2H),7.65–7.49(m,2H),7.46(t,J=7.6Hz,1H),7.25(d,J=8.6Hz,1H),6.56(d,J=8.6Hz,1H),6.22(s, 1H),5.85(s,2H),1.29(s,3H),1.13(s,2H).MS(ESI,m/z):C21H17F3N2O,[M+H]+371.13.
实施例24:
THU124:1H NMR(400MHz,Chloroform-d)δ8.23(d,J=8.4Hz,1H),7.79(d,J=8.1Hz,1H),7.64–7.53(m,2H), 7.49(t,J=7.5Hz,1H),7.18–7.01(m,3H),6.45(d,J=2.1Hz,2H),5.57(s,1H),3.57(s,2H),1.79(d,J=1.9Hz,3H), 1.69(s,2H),1.20(s,2H).13CNMR(101MHz,Chloroform-d)δ144.07,138.46,134.30,133.72,132.54,131.28,129.04,128.30,127.50,126.45,125.59,125.57,124.56,123.09,118.52,116.19,36.85,18.27.MS(ESI,m/z):C20H20N2O2S, [M+H]+353.13.
实施例25:
THU125:1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.69(d,J=8.0Hz,1H),8.23–7.96(m,3H),7.93(d, J=7.6Hz,1H),7.81(t,J=7.9Hz,2H),7.62–7.42(m,3H),6.96(d,J=7.9Hz,1H),6.75(d,J=7.9Hz,1H), 6.52(s,1H),3.50–3.41(m,2H),2.86(s,2H),2.80(s,3H),1.90(s,3H),1.37(s,2H),1.17(s,2H).13C NMR(101 MHz,DMSO-d6)δ170.12,138.35,138.08,133.93,132.28,131.44,128.90,128.85,128.09,126.13,125.89,125.70,125.51,50.08,36.15,34.58,18.36,14.57.MS(ESI,m/z):C24H27N3O,[M+H]+374.22.
实施例26:
THU126:1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.69(d,J=8.4Hz,3H),7.98–7.90(m,1H),7.82(t, J=8.3Hz,2H),7.64–7.43(m,3H),6.96(d,J=8.5Hz,1H),6.74(dd,J=8.5,2.8Hz,1H),6.49(d,J=2.8Hz, 1H),3.49(t,J=6.9Hz,2H),2.96(q,J=6.6Hz,2H),2.79(s,3H),2.54(d,J=5.3Hz,3H),1.92(s,3H),1.37(q,J =4.4Hz,2H),1.18(t,J=3.3Hz,2H).13C NMR(101MHz,DMSO-d6)δ170.18,138.08,133.93,132.28,131.43, 128.91,128.10,126.15,125.89,125.68,125.52,48.85,45.51,34.58,33.09,18.36,14.57.MS(ESI,m/z): C25H29N3O,[M+H]+424.20.
实施例27:
THU127:1H NMR(400MHz,Methanol-d4)δ8.61(d,J=8.4Hz,1H),7.91(dd,J=7.2,1.4Hz,2H),7.82(d, J=8.2Hz,1H),7.61–7.55(m,1H),7.51(td,J=7.4,6.7,1.2Hz,1H),7.46(dd,J=8.3,7.1Hz,1H),7.00(d,J=8.5Hz,1H),6.69(dd,J=8.6,2.8Hz,1H),6.40(d,J=2.8Hz,1H),3.40(t,J=6.9Hz,4H),2.54(s,4H),2.32(s, 12H),2.00(s,3H),1.46(t,J=3.5Hz,2H),1.32(q,J=4.7Hz,2H).MS(ESI,m/z):C29H38N4O,[M+H]+459.31.
实施例28:
THU128:1H NMR(400MHz,Methanol-d4)δ8.64(d,J=8.5Hz,1H),8.33(d,J=21.6Hz,1H),7.96–7.87 (m,2H),7.82(dd,J=7.9,4.5Hz,1H),7.60(dddd,J=8.4,6.8,2.9,1.4Hz,1H),7.55–7.45(m,2H),7.38(d,J= 1.8Hz,1H),2.20(d,J=17.9Hz,3H),1.49(td,J=7.8,7.3,2.9Hz,2H),1.33(dt,J=11.6,5.6Hz,2H).13C NMR (101MHz,Methanol-d4)δ172.29,141.94,136.76,134.18,132.62,132.12,130.74,128.40,128.34,127.87,125.66, 125.11,124.70,115.31,113.93,34.27,18.31,13.52.MS(ESI,m/z):C22H19N3O,[M+H]+342.41.
实施例29:
THU129:1H NMR(400MHz,Methanol-d4)δ8.61(d,J=8.5Hz,1H),7.91(dt,J=7.0,2.7Hz,2H),7.83(d,J =8.3Hz,1H),7.62(t,J=7.8Hz,1H),7.57–7.41(m,2H),7.09(d,J=8.1Hz,1H),6.90(dd,J=8.2,2.7Hz,1H), 6.67(d,J=2.5Hz,1H),4.53(q,J=6.9,6.5Hz,1H),4.31(t,J=9.6Hz,2H),4.14(dd,J=10.9,6.5Hz,2H),1.99 (d,J=2.4Hz,3H),1.50(s,2H),1.32(d,J=7.8Hz,2H).13C NMR(101MHz,Methanol-d4)δ171.86,139.27, 137.44,136.49,134.16,132.07,131.62,129.01,128.42,128.00,125.81,125.22,124.70,124.43,117.64,114.42, 51.80,47.30,34.38,16.97,13.54.MS(ESI,m/z):C24H25N3O,[M+H]+372.46.
实施例30:
THU130:1H NMR(400MHz,Methanol-d4)δ8.60(d,J=8.4Hz,1H),7.90(d,J=7.6Hz,2H),7.81(d,J= 8.2Hz,1H),7.59(t,J=7.7Hz,1H),7.51(t,J=7.5Hz,1H),7.44(t,J=7.7Hz,1H),6.89(d,J=8.3Hz,1H),6.59 (d,J=8.3Hz,1H),6.38(s,1H),3.41(d,J=18.7Hz,3H),3.15–3.06(m,1H),2.83(s,3H),2.10(d,J=13.8Hz, 2H),1.94(s,3H),1.57(d,J=21.0Hz,2H),1.46(d,J=5.6Hz,2H),1.30(d,J=5.4Hz,2H).MS(ESI, m/z):C27H31N3O,[M+H]+414.36.
实施例31:
THU131:1H NMR(400MHz,MeOD)δ8.61(d,J=8.5Hz,1H),7.94–7.86(m,2H),7.81(d,J=8.2Hz,1H), 7.58(t,J=7.7Hz,1H),7.51(t,J=7.5Hz,1H),7.48–7.41(m,1H),6.88(d,J=8.1Hz,1H),6.58(dd,J=8.2,2.6 Hz,1H),6.35(d,J=2.5Hz,1H),3.35–3.31(m,2H),3.26(d,J=10.9Hz,1H),3.11(d,J=12.8Hz,2H),2.71(t, J=12.2Hz,2H),1.96(d,J=2.1Hz,5H),1.44(d,J=5.7Hz,2H),1.30(s,2H).13C NMR(101MHz,MeOD)δ 172.88,145.07,137.40,136.86,134.16,132.12,130.80,128.37,128.27,127.81,125.60,125.09,124.71,124.52, 114.76,111.47,48.91,46.97,43.91,34.11,31.18,16.72,13.49.MS(ESI,m/z):C26H29N3O,[M+H]+400.23.
实施例32:
THU132:1H NMR(400MHz,MeOD)δ8.61(d,J=8.5Hz,1H),7.95–7.89(m,2H),7.84(d,J=8.2Hz,1H), 7.60(ddd,J=8.4,6.9,1.3Hz,1H),7.49(ddd,J=21.5,8.0,6.8Hz,2H),7.24(s,2H),7.01(s,1H),4.41–4.31(m, 1H),3.59(ddd,J=27.7,12.4,7.3Hz,2H),3.48–3.36(m,2H),2.38(dq,J=14.6,7.4Hz,1H),2.21(dq,J=13.7, 7.1Hz,1H),2.06(s,3H),1.50(q,J=4.8Hz,2H),1.36–1.31(m,2H).13C NMR(101MHz,MeOD)δ170.80, 138.39,136.57,134.16,132.07,131.91,128.44,128.40,127.96,125.76,125.17,124.71,124.41,120.56,117.66, 57.00,44.37,34.25,28.18,17.17,13.57.MS(ESI,m/z):C25H27N3O,[M+H]+386.22.
实施例33:
THU133:1H NMR(400MHz,MeOD)δ8.60(d,J=8.4Hz,1H),7.94–7.89(m,2H),7.83(d,J=8.3Hz,1H), 7.58(t,J=7.6Hz,1H),7.47(ddd,J=25.3,12.5,5.0Hz,3H),7.25(d,J=2.4Hz,1H),7.12(d,J=8.3Hz,1H), 2.05(s,3H),1.66(d,J=7.2Hz,2H),1.50–1.40(m,4H),1.33(d,J=5.8Hz,2H).13C NMR(101MHz,MeOD)δ 171.60,167.98,137.12,136.68,134.84,134.13,132.08,131.53,130.51,128.38(d,J=5.5Hz),127.90,125.69, 125.14,124.70,124.43,122.30,119.54,35.50,34.15,17.21,13.64,12.05.MS(ESI,m/z):C25H25N3O2,[M+H] +400.19.
实施例34:
THU134:1H NMR(400MHz,CDCl3)δ8.46(d,J=8.0Hz,1H),7.95(d,J=6.5Hz,1H),7.91(d,J=7.5Hz, 1H),7.82(d,J=8.0Hz,1H),7.59–7.43(m,3H),7.08–6.93(m,3H),6.83(s,1H),6.54(s,1H),6.34(d,J=7.4 Hz,1H),6.29–6.20(m,2H),2.12(s,3H),1.60–1.51(m,2H),1.43–1.35(m,2H).13C NMR(101MHz,CDCl3)δ 169.77,147.52,144.20,140.67,137.30,136.86,133.99,131.91,131.68,130.22,129.01,128.74,128.33,128.09,126.19,125.51,125.49,124.08,119.83,116.88,108.06,107.92,103.66,34.81,18.69,14.83.MS(ESI, m/z):C27H25N3O,[M+H]+408.20.
实施例35:
THU135:1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),9.01(s,1H),8.65(d,J=8.1Hz,1H),8.07(s,1H), 7.93(d,J=7.2Hz,1H),7.82(d,J=6.2Hz,2H),7.57–7.37(m,4H),7.07(t,J=8.0Hz,1H),6.94(d,J=7.9Hz, 1H),6.78(s,1H),6.64(d,J=8.0Hz,1H),2.02(s,3H),1.98(s,3H),1.40–1.29(m,2H),1.20–1.14(m,2H).13C NMR(101MHz,CDCl3)δ170.09,168.50,144.07,139.60,138.59,137.19,136.41,133.96,132.04,129.90,129.74,128.88,128.77,128.04,125.69,125.38,125.25,124.65,120.82,117.74,112.87,110.75,107.47,34.83,24.82,19.10, 14.58.MS(ESI,m/z):C29H27N3O2,[M+H]+450.21.
上述实施例化合物的制备:
(1)环丙基胺中间体(1-(萘-1-基)环丙胺)的制备,合成路线如下:
具体操作如下所示:
将1-萘甲腈(1,5mmol,1.0e.q.)置于圆底烧瓶中,加入10mL干燥的四氢呋喃作为溶剂,随后加入钛酸四异丙酯(5.5mmol,1.0e.q.),将反应体系降温至-78℃,然后向反应体系中缓慢滴加乙基格氏试剂(11 mmol,2.2e.q.)。滴加完成后,将反应体系升温至室温反应1.5小时。随后向反应体系中滴加三氟化硼乙醚 (10mmol,2.0e.q.),滴加完成后常温下搅拌反应三小时。反应结束后向反应体系中滴加2N盐酸20mL,搅拌淬灭20分钟,随后加入过量的饱和氢氧化钠溶液。加入乙酸乙酯萃取,收集有机相并旋干后通过硅胶柱层析分离,既可获得环丙基胺中间体2。
(2)实施例24的化合物的制备,合成路线如下:
具体操作为:将化合物2(1.0mmol,1.0e.q.)置于圆底烧瓶内,加入10mL THF作溶剂,加入三乙胺(4.0e.q.), 0℃下滴加化合物3(1.0mmol,1.0e.q.)的THF溶液,滴加完毕后撤去冰浴,50℃搅拌反应12h。待反应结束后,旋干溶剂,加入乙酸乙酯和水萃取,用饱和氯化铵溶液洗涤一次,饱和食盐水洗涤一次,有机相旋干,硅胶柱层析纯化得到产物THU124。
(3)实施例28的化合物的制备,合成路线如下:
将中间体4与先前得到的三元环胺中间体2按照一比一当量加入DMF溶剂,加入HATU(1.5e.q.)和 DIPEA(2.0e.q.),70℃下反应12h,乙酸乙酯萃取反应液,用饱和氯化铵溶液洗涤三次,有机相旋干后,硅胶柱层析纯化得到产物THU128。
(4)其他实施例化合物的制备,合成路线如下:
具体操作为:
将中间体M1(1.0e.q.)置于圆底烧瓶,加入四氢呋喃:水=2:1作为溶剂,随后向反应体系中加入氢氧化锂(4.0e.q.),60℃搅拌反应6小时后将反应体系用2N盐酸酸化,加入乙酸乙酯后既析出白色固体,抽滤出固体并干燥后既得到中间体M2。
将中间体M2与先前得到的三元环胺中间体2按照一比一当量加入DMF溶剂,加入HATU(1.5e.q.)和 DIPEA(2.0e.q.),70℃下反应12h,乙酸乙酯萃取反应液,用饱和氯化铵溶液洗涤三次,有机相旋干后,硅胶柱层析纯化得到产物P。
上中R1为环上一个或多个独立的取代基,R1、Y1、Y2、Y3、Y4根据具体化合物结构选择。
例如对于化合物THU116、THU117、THU118、THU125、THU126、THU127、THU129、THU130、THU131、 THU132、THU134、THU135,中间体M1为其合成路线如下:
其中,R2=H、-CH3、-SO2CH3或-CH2CH2N(CH3)2;
R3=-CH3、-CONH2、-SO2CH3、-SO2NH2、-CH2CH2NH2、-CH2CH2NH(CH3)、-CH2CH2N(CH3)2、
具体操作为:将2-甲基-5-溴苯甲酸甲酯(5,10.0mmol,1.0e.q.)、胺类化合物(6,10.0mmol,1.0e.q.)、三(二亚苄基丙酮)二钯(0.2mmol,0.02e.q.)、2-二环己基磷-2,4,6-三异丙基联苯(0.8mmol,0.08e.q.)、碳酸铯(20.0mmol,2.0e.q.)置于密封管内,加入50mL甲苯作为溶剂,在氩气保护下110℃持续搅拌反应 24h。反应结束后将反应液移至圆底烧瓶内,旋干溶剂,加入乙酸乙酯和水萃取,有机相用饱和氯化铵溶液、饱和食盐水各洗涤一次,旋干有机相,硅胶柱层析纯化得到中间体M1。
实验实施例1:检测上述实施例制备的化合物的PLpro抑制活性
生物测试条件:
1、Reaction buffer:20mM HEPEs,pH 7.5,100mM NaCl,1mM TCEP
2、母液配制:
(1)20μM Ub-AMC(Ub-AMC干粉直接用reaction buffer溶解,离心去除沉淀后使用);
(2)400nM PLpro(分子筛纯化后冻存至-80℃,用前冰上融化,用reaction buffer稀释);
(3)40μM试验化合物(试验化合物干粉用DMSO溶解至40mM;用50%DMSO稀释至400μM;再用reaction buffer稀释至40μM);
3、对于单点抑制试验反应体系:10μM Ub-AMC,100nM PLpro,1μM试验化合物,总体积20μL,384孔板内反应;
将5μL PLpro母液+5μL试验化合物母液,加入384孔板后,4℃孵育30min;
将10μL Ub-AMC母液加入384孔板,37℃反应30min后测AMC荧光强度(excitation:360nm;emission:460 nm);
4、+Control:对应稀释倍数的DMSO代替试验化合物;
Blank:Reaction buffer替代PLpro;
5、数据处理:将测得数值减去Blank值,以DMSO数值为基准做归一化;
6、IC50测定:
试验化合物浓度梯度(nM):10000,5000,1000,500,250,125,62.5,31.25,15.625,10,5,2,1,0.5, 0.1,0.01
反应15min测荧光值(15min左右酶反应速率处于线性区间,30min非线性区间);
7、数据拟合:数据归一化后用Sigmaplot处理(拟合方程:Logistic,3Parameter)。
结果如下表所示。
表1实验结果
其中GRL0617为阳性参照,是文献中报道的对PLpro抑制活性最强的一类分子代表(Ghosh et al.,2009; Ghosh et al.,2010;Ratia et al.,2008)。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换等,均应包含在本发明的保护范围之内。
本发明中描述的前述实施例和方法可以基于本领域技术人员的能力、经验和偏好而有所不同。
本发明中仅按一定顺序列出方法的步骤并不构成对方法步骤顺序的任何限制。
Claims (16)
1.一种化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物,所述化合物具有以下结构:
其中,
Ar选自:萘基、喹啉基、异喹啉基和喹唑啉基,其中萘基、喹啉基、异喹啉基或喹唑啉基中的氢原子可以任选地被C1-C6烷基、-NH2、-OH、-OC1-C6烷基、-CH2X、-CHX2、-CX3取代;
L1选自:C1-C6亚烷基、-CO-、-SO2-;
A1、A2、A3、A4和A5独立地选自C或N,且当A1、A2、A3、A4或A5为N原子时,与之相连的R1、R2、R3、R4或R5不存在;
R1、R2、R3、R4和R5独立地选自:H、C1-C6烷基、-L2-NR9R10、-L2-OH、-L2-OC1-C6烷基、-CN、-X、-CH2X、-CHX2、-CX3;或者,R1、R2、R3、R4和R5中的两者与其连接的原子一起形成杂环基;
L2选自:单键、C1-C6亚烷基、-CO-、-SO2-、-NHCO-、-NH-SO2-;
R9和R10独立地选自:H、C1-C6烷基、-CH2X、-CHX2、-SO2(C1-C6烷基)、-CX3、-L3-NR11R12、含氮杂环基;
R11和R12独立地选自:H、C1-C6烷基、-CH2X、-CHX2、-SO2(C1-C6烷基)、-CX3、-CO(C1-C6烷基);
X选自:F、Cl、Br、I;
R6选自:H、C1-C6烷基;
W1和W2独立地选自:C、N、O;且当W1或W2为O时,相应的R7或R8不存在;
R7和R8独立地选自:H、(=O)、C1-C6烷基、-X、-CH2X、-CHX2、-CX3、羟基、-OC1-C6烷基。
2.如权利要求1所述的化合物,其特征在于,Ar选自:1-萘基、2-萘基、2-喹啉基、3-喹啉基、4-喹啉基、5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、1-异喹啉基、3-异喹啉基、4-异喹啉基、5-异喹啉基、6-异喹啉基、7-异喹啉基、8-异喹啉基、2-喹唑啉基、4-喹唑啉基、5-喹唑啉基、6-喹唑啉基、7-喹唑啉基、8-喹唑啉基;
优选地,Ar为1-萘基或2-萘基。
3.如权利要求1或2所述的化合物,其特征在于,A1、A2、A3、A4和A5均为C;或,
A1为N,A2、A3、A4和A5为C;或,
A2为N,A1、A3、A4和A5为C;或,
A3为N,A1、A2、A4和A5为C;或,
A4为N,A1、A2、A3和A5为C;或,
A5为N,A1、A2、A3和A4为C;或,
A1和A2为N,A3、A4和A5为C;或,
A1和A3为N,A2、A4和A5为C;或,
A1和A4为N,A2、A3和A5为C;或,
A1和A5为N,A2、A3和A4为C;或,
A2和A3为N,A1、A4和A5为C;或,
A2和A4为N,A1、A3和A5为C;或,
A2和A5为N,A1、A3和A4为C;或,
A3和A4为N,A1、A2和A5为C;或,
A3和A5为N,A1、A2和A4为C;或,
A4和A5为N,A1、A2和A3为C。
4.如权利要求1-3任一项所述的化合物,其特征在于,W1为C,W2为C;或,W1为C,W2为N;或,W1为C,W2为O。
5.如权利要求1-4任一项所述的化合物,其特征在于,R7和R8独立地选自:H、(=O)、C1-3烷基、-CF3、羟基;优选地,R7和R8均为H。
7.如权利要求1-6任一项所述的化合物,其特征在于,L1为-CO-或-SO2-。
8.如权利要求1-7任一项所述的化合物,其特征在于,R6选自:H、-CH3、-CH2CH3。
13.一种药物组合物,其包含权利要求1-12任一项所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物,以及一种或多种药学上可接受的辅料。
14.权利要求1-12任一项所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物、权利要求13所述的药物组合物在制备预防和/或治疗由病毒感染引起或病毒感染相关的疾病或病症的药物中的应用。
15.如权利要求14所述的应用,其特征在于,所述病毒为冠状病毒,例如,HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU、SARS-CoV、MERS-CoV、SARS-CoV-2。
16.如权利要求14所述的应用,其特征在于,所述疾病或病症为COVID-19、SARS或MERS。
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2023064493A1 (en) * | 2021-10-13 | 2023-04-20 | Clear Creek Bio, Inc. | Compounds and methods for treating coronaviruses |
WO2023208171A1 (zh) * | 2022-04-29 | 2023-11-02 | 清华大学 | PLpro蛋白抑制剂及其制备方法和应用 |
WO2023208170A1 (zh) * | 2022-04-29 | 2023-11-02 | 清华大学 | 蛋白酶抑制剂及其制备方法和应用 |
WO2024040497A1 (zh) * | 2022-08-25 | 2024-02-29 | 清华大学 | 一种抗病毒化合物及其制备方法和应用 |
WO2024121779A1 (en) * | 2022-12-09 | 2024-06-13 | Pfizer Inc. | Papain-like protease (plpro) inhibitors |
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Publication number | Priority date | Publication date | Assignee | Title |
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WO2023064493A1 (en) * | 2021-10-13 | 2023-04-20 | Clear Creek Bio, Inc. | Compounds and methods for treating coronaviruses |
WO2023208171A1 (zh) * | 2022-04-29 | 2023-11-02 | 清华大学 | PLpro蛋白抑制剂及其制备方法和应用 |
WO2023208170A1 (zh) * | 2022-04-29 | 2023-11-02 | 清华大学 | 蛋白酶抑制剂及其制备方法和应用 |
WO2024040497A1 (zh) * | 2022-08-25 | 2024-02-29 | 清华大学 | 一种抗病毒化合物及其制备方法和应用 |
WO2024121779A1 (en) * | 2022-12-09 | 2024-06-13 | Pfizer Inc. | Papain-like protease (plpro) inhibitors |
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